Amlodipine is 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate and has been used in the treatment of ischemic and hypertensive heart diseases as a calcium-channel blocker. Furthermore, it has been well known that amlodipine is an effective and useful agent due to its prolonged activity.
Amlodipine was first disclosed as a novel compound of 1,4-dihydropyridines in EP Patent Publication No. 89,167. This patent teaches that pharmaceutically acceptable salts of amlodipine can be produced from non-toxic acids with pharmaceutically acceptable anions such as chloride, bromide, sulfate, phophate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and more preferably maleate.
Free form of amlodipine is also pharmaceutically useful, but it has been administered in the salt form of a pharmaceutically acceptable acid due to its low stability.
Korean Patent No. 90,479 discloses four physicochemical properties, which are required to form pharmaceutically acceptable salts: (1) excellent aqueous solubility; (2) excellent stability; (3) non-hygroscopicity; and (4) processability for tablet formulation. It is, however, very difficult to meet all the four physicochemical property requirements above, and even the maleate salt, which is currently the most preferable pharmaceutical form, has been reported to decompose in the solution within several weeks.
Korean Patent No. 91,020 discloses that amlodipine besylate is superior over conventional salts of amlodipine and has excellent processability for pharmaceutical formulation. However, it has been brought for safety issues since benzenesulfonic acid, which is corrosive and toxic, is used in the process for producing amlodipine besylate.